title: Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.
abstract: Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.
authors.affiliation: LEGENDO, K.U. Leuven, B-3000 Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.forename: Noelia
authors.initials: N
authors.lastname: Valle
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sato
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Pierre
authors.initials: P
authors.lastname: De Clercq
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000819:agonists* / Q000031:analogs & derivatives* / Q000737:chemistry; D018360:Crystallography, X-Ray; D017611:Fluorine Compounds / Q000819:agonists* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D017611:Fluorine Compounds; D018167:Receptors, Calcitriol; D051820:TCF Transcription Factors; D051176:beta Catenin; D002762:Cholecalciferol